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Docking of competitive inhibitors to the P2X7 receptor family reveals key differences responsible for changes in response between rat and human.

Caseley EA, Muench SP, Baldwin SA, Simmons K, Fishwick CW, Jiang LH - Bioorg. Med. Chem. Lett. (2015)

Bottom Line: Importantly this residue is replaced by Leu in the rat P2X7 receptor resulting in a significantly reduced binding affinity.This work provides new insights into binding of P2X7 inhibitors and shows the structural difference in human and rat P2X7 receptors which results in a difference in affinity.Such information is useful both for the rational design of inhibitors based on these scaffolds and also the way in which these compounds are tested in animal models.

View Article: PubMed Central - PubMed

Affiliation: School of Biomedical Sciences, University of Leeds, Leeds, UK. Electronic address: bs09e2c@leeds.ac.uk.

No MeSH data available.


Related in: MedlinePlus

Predicted antagonist binding site in relation to the known ATP binding site. (A) Docking of SB203580 and ATP into the human P2X7 receptor, with residues proximal to the antagonist binding site shown in purple. (B) Enlarged view of the antagonist binding region highlighted in purple.
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f0005: Predicted antagonist binding site in relation to the known ATP binding site. (A) Docking of SB203580 and ATP into the human P2X7 receptor, with residues proximal to the antagonist binding site shown in purple. (B) Enlarged view of the antagonist binding region highlighted in purple.

Mentions: To this end we investigated the mode of binding of this family of P2X7 antagonist inhibitors based on in silico approaches. Structural models of P2X receptors were produced based on the zebrafish P2X4 crystal structure in the closed state (Protein Data Bank code 4DW0) using Modeller version 9.1231,32 (Fig. 1A). Docking studies were carried out using AutoDock version 4.2.33 All necessary files were prepared using AutoDock tools. The target cavity file for each docking simulation consisted of a 15 Å sphere in the extracellular domain of the P2X7 receptor, centred around the amino acid at position 95, since this had previously been reported to be involved in binding.34,35 Ligands were docked using standard parameters and a standard Lamarckian genetic algorithm. Dockings were visualised using AutoDock tools and were clustered using 2 Å RMS. The most populated/lowest energy poses were examined.


Docking of competitive inhibitors to the P2X7 receptor family reveals key differences responsible for changes in response between rat and human.

Caseley EA, Muench SP, Baldwin SA, Simmons K, Fishwick CW, Jiang LH - Bioorg. Med. Chem. Lett. (2015)

Predicted antagonist binding site in relation to the known ATP binding site. (A) Docking of SB203580 and ATP into the human P2X7 receptor, with residues proximal to the antagonist binding site shown in purple. (B) Enlarged view of the antagonist binding region highlighted in purple.
© Copyright Policy - CC BY
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4508345&req=5

f0005: Predicted antagonist binding site in relation to the known ATP binding site. (A) Docking of SB203580 and ATP into the human P2X7 receptor, with residues proximal to the antagonist binding site shown in purple. (B) Enlarged view of the antagonist binding region highlighted in purple.
Mentions: To this end we investigated the mode of binding of this family of P2X7 antagonist inhibitors based on in silico approaches. Structural models of P2X receptors were produced based on the zebrafish P2X4 crystal structure in the closed state (Protein Data Bank code 4DW0) using Modeller version 9.1231,32 (Fig. 1A). Docking studies were carried out using AutoDock version 4.2.33 All necessary files were prepared using AutoDock tools. The target cavity file for each docking simulation consisted of a 15 Å sphere in the extracellular domain of the P2X7 receptor, centred around the amino acid at position 95, since this had previously been reported to be involved in binding.34,35 Ligands were docked using standard parameters and a standard Lamarckian genetic algorithm. Dockings were visualised using AutoDock tools and were clustered using 2 Å RMS. The most populated/lowest energy poses were examined.

Bottom Line: Importantly this residue is replaced by Leu in the rat P2X7 receptor resulting in a significantly reduced binding affinity.This work provides new insights into binding of P2X7 inhibitors and shows the structural difference in human and rat P2X7 receptors which results in a difference in affinity.Such information is useful both for the rational design of inhibitors based on these scaffolds and also the way in which these compounds are tested in animal models.

View Article: PubMed Central - PubMed

Affiliation: School of Biomedical Sciences, University of Leeds, Leeds, UK. Electronic address: bs09e2c@leeds.ac.uk.

No MeSH data available.


Related in: MedlinePlus